Assessing causality of the association between maternal smoking during pregnancy and offspring intellectual disability

Student thesis: Doctoral ThesisDoctor of Philosophy (PhD)


Maternal smoking has known adverse effects on fetal development. However, research on the association between maternal smoking during pregnancy and offspring intellectual disability (ID) is limited, and whether any associations are due to a causal effect or residual confounding is unclear.
The association was investigated using two intergenerational cohorts, each with over 1 million individuals with data held in the Danish and Swedish registers, and using a prospectively collected pregnancy cohort of approximately 15,000 mother and child pairs in the United Kingdom. Observational analyses were performed in each cohort using regression analyses adjusted for potential confounders. Sibling comparisons, negative control analyses, and Mendelian randomisation (MR) were used to provide evidence about the causal nature of the association. Simulation studies were conducted to investigate the nature of biases arising from assortative mating in the negative control design and from the proportion of missing data in multiple imputation analyses, a method to account for missing data.
Observational analyses provided evidence for an increased risk of ID in children of mothers who smoked during pregnancy. Sibling comparison models decomposed this population averaged effect to reveal a null within-family effect while negative control analyses showed comparable effect estimates for maternal and paternal smoking during pregnancy. MR analyses also did not provide evidence of a causal effect.
The results of analyses contained within this thesis are not consistent with a causal effect of maternal smoking during pregnancy on offspring risk of ID. By combining evidence across different analysis methods, results suggest that prior observational associations were the result of unmeasured genetic or environmental characteristics of families in which the mother smokes during pregnancy.
Date of Award23 Mar 2021
Original languageEnglish
Awarding Institution
  • The University of Bristol
SponsorsWellcome Trust
SupervisorDheeraj Rai (Supervisor), Stanley Zammit (Supervisor) & Jon E Heron (Supervisor)


  • Smoking
  • Causal inference
  • Intellectual disability
  • Confounding
  • Prenatal

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